EP3105220B1 - Procédé de fabrication de dérivés de pyrimidine sulfonamide - Google Patents

Procédé de fabrication de dérivés de pyrimidine sulfonamide Download PDF

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EP3105220B1
EP3105220B1 EP15706185.4A EP15706185A EP3105220B1 EP 3105220 B1 EP3105220 B1 EP 3105220B1 EP 15706185 A EP15706185 A EP 15706185A EP 3105220 B1 EP3105220 B1 EP 3105220B1
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compound
formula
salt
reaction
mixture
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EP3105220A1 (fr
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Stefan Abele
Jacques-Alexis Funel
Ivan SCHINDELHOLZ
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Idorsia Pharmaceuticals Ltd
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Idorsia Pharmaceuticals Ltd
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Priority to EP17159638.0A priority Critical patent/EP3214082B1/fr
Priority to SI201531349T priority patent/SI3105220T1/sl
Priority to PL15706185T priority patent/PL3105220T3/pl
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a process for manufacturing the pyrimidine sulfamide derivatives of formula I wherein R represents H.
  • the compounds of formula I are endothelin receptor antagonists which have been first disclosed in WO 02/053557 .
  • macitentan compound of formula I wherein R is n -propyl; chemical names: N -[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]- N '-propylsulfamide or N -[5-(4-bromophenyl)-6- ⁇ 2-[(5-bromopyrimidin-2-yl)oxy]ethoxy ⁇ pyrimidin-4-yl]- N '-propylsulfuric diamide) is an endothelin receptor antagonist that is notably approved by the US Food and Drug Administration and the European Commission for the treatment of pulmonary arterial hypertension.
  • the last step of one of the potential preparation routes described in WO 02/053557 called "Possibility A" and "Pos
  • G 1 represents a reactive residue, and preferentially a chloro atom.
  • G 2 represents a reactive group such as a halogen atom (preferably a chlorine atom) and PG represents a protecting group such as a benzyl group or a 4-methoxy- or a 2,4-dimethoxybenzyl group.
  • the compound of formula I 0 can be reacted with ethylene glycol in the presence of a base, in the presence or absence of an additional solvent and preferably at elevated temperatures.
  • the resulting intermediate can then be reacted with 5-bromo-2-chloropyrimidine or an equivalent reactive entity in the presence of a strong base in a solvent such as THF, DMF, dioxane, etc. or mixtures thereof.
  • the protecting group PG can then be removed by standard methods to yield the compound of formula I wherein R is H.
  • reaction of the compound of formula I-1 wherein X is chlorine with standard fluorinating agents such as KF or NaF did not yield the fluorinated intermediate with sufficient purity and yield.
  • reaction of the compound of formula I-1 wherein X is chlorine with sulfamide did not occur at 70°C in DMSO.
  • a significant advantage of this alternative route is that it allows the use in the last step of a pyrimidine derivative already possessing a functionalised side chain at position 6 (i.e. the 2-(5-bromo-pyrimidin-2-yloxy)-ethoxy side chain), which avoids the use of an excess of ethylene glycol (required at some point to obtain the 2-(5-bromo-pyrimidin-2-yloxy)-ethoxy side chain - see e.g. WO 02/053557 or Bolli et al., J. Med. Chem. (2012), 55, 7849-7861 ) in a late stage of the manufacturing process.
  • this route allows to use a single intermediate for preparing in a single step any compound of formula I wherein R represents H, (C 1 -C 6 )alkyl or benzyl.
  • the compound of formula I-1 can be prepared as summarized in Scheme 1 hereafter.
  • 5-bromo-2-chloropyrimidine (compound I A ) can be reacted (Scheme 1) with ethylene glycol in the presence of a base (e.g. tBuOK or DBU), affording 2-((5-bromopyrimidin-2-yl)oxy)ethanol (compound I B ).
  • a base e.g. tBuOK or DBU
  • Another method for obtaining the compound I B would be to perform the reaction of 5-bromo-2-chloropyrimidine with 2-( tert -butoxy)ethanol in the presence of a base such as tBuOK and then the removal of the tert -butyl protecting group either by using conc. aq.
  • the compound of formula I-1 wherein X is F can be reacted with TBAF hydrate in the presence or the absence of a base in a polar aprotic solvent.
  • the compound of formula I C wherein X is Br or Cl can be prepared by methods similar either to those described in Bolli et al., J. Med. Chem. (2012), 55, 7849-7861 or to those described in WO 2010/091824 .
  • the compound of formula 1-2 is either commercial (when R is H) or can be prepared by methods similar to those described in Bolli et al., J. Med. Chem. (2012), 55, 7849-7861 for obtaining the compound of formula 1-2 wherein R is n -propyl (when R is (C 1 -C 6 )alkyl or benzyl).
  • the compound of formula I-1 wherein X is Br or Cl can notably be used either for obtaining directly the compounds of formula I (see for example embodiment 1) above) or for obtaining the compound of formula I-1 wherein X is F (by reaction with TBAF in the presence or the absence of a base).
  • the compound of formula I-1 wherein X is F can notably be used for obtaining the compounds of formula I (see for example embodiment 1) above).
  • Example 2 The compound of Example 1 (20.0 g; 41.1 mmol; 1.0 eq.) and cesium fluoride (7.5 g; 49.3 mmol; 1.2 eq.) were suspended in DMSO (200 mL). It was heated to 70-75°C over 4 h. The brown reaction mixture was cooled to 20-25°C. It was diluted with EA (140 mL), washed with water (140 mL), a 10% aq. citric acid solution (140 mL) and brine (140 mL). It was concentrated to dryness to afford the title compound as a crude yellow solid. This material was suspended in iPrOH (40 mL) and heated to reflux for 10 min.
  • Example 1 The compound of Example 1 (5.0 g; 10.3 mmol; 1.0 eq.) and TBAF.3H 2 O (5.4 g; 17.0 mmol; 1.7 eq.) were suspended in DMSO (50 mL). The mixture was stirred at 20-25°C for 6 h. EA was added (50 mL), followed by a sat. aq. solution of CaCl 2 (10 mL). The layers were separated and the org. phase was washed 3 times with brine (50 mL each time), then once with water (25 mL). The org. phase was concentrated under reduced pressure to dryness. The residue was recrystallized from iPrOH (10 mL) and THF (1.25 mL) to afford the title product as a white powder (3.2 g, 66% yield).
  • Example 1 A reactor was charged with compound of Example 1 (600 g; 1.23 mol; 1.0 eq.), cesium fluoride (562 g; 3.69 mol; 3.0 eq.), DMSO (3 L) and toluene (1.2 L). The toluene was distilled off, and the remaining mixture was stirred at 70 °C for 2 h. After cooling to RT, EA (2.4 L) and water (2.4 L) were added. The layers were separated, and the org. layer was successively washed with 7.5% w/v CaCl 2 solution (2.4 L), brine (2.4 L) and water (3 L).
  • Example 3 preparation of ⁇ 5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl ⁇ -sulfamide:
  • Example 2 The compound of Example 1 (25 g; 51.4 mmol), sulfamide (5.4 g; 56.5 mmol; 1.1 eq.), TBAF.3H 2 O (48.6 g, 154 mmol, 3 eq.) and potassium carbonate (21.3 g, 154 mmol, 3 eq.) were suspended in DMSO (250 mL) at 20-25°C. The mixture was heated to 70-75°C for 1 h. At this point, LC-MS indicated complete conversion. The reaction mixture was cooled to 10-15°C. Water (200 mL) and DCM (350 mL) were added (caution: exotherm). The layers were separated and the org. phase was washed twice with water (200 mL).
  • Example 2 The compound of Example 1 (10 g; 20.6 mmol), sulfamide (2.2 g; 56.5 mmol; 1.1 eq.), TBAF.3H 2 O (16.2 g, 51.4 mmol, 2.5 eq.) and potassium carbonate (7.1 g; 51.4 mmol; 2.5 eq.) were suspended in DMSO (50 mL) at 20-25°C. The mixture was heated to 70-75°C for 1 h. At this point, LC-MS indicated complete conversion. The reaction mixture was cooled to 10-15°C. Water (100 mL) and DCM (100 mL) were added (caution: exotherm). The layers were separated and the org.
  • Example 1 The compound of Example 1 (100 g; 206 mmol), sulfamide (21.7 g; 226 mmol; 1.1 eq.), TBAF.3H 2 O (162 g; 514 mmol; 2.5 eq.) and potassium carbonate (71 g; 514 mmol; 2.5 eq.) were suspended in DMSO (500 mL) at 20-25°C. The mixture was heated to 70-75°C for 2 h. At this point, LC-MS indicated complete conversion. The reaction mixture was cooled to 10-15°C. Water (1 L) and EA (1 L) were added (caution: exotherm). The layers were separated and the org. phase was washed with brine (1 L).
  • Example 2 The compound of Example 2 (2 g; 4.25 mmol), sulfamide (0.45 g; 4.68 mmol; 1.1 eq.) and potassium carbonate (1.5 g; 10.6 mmol; 2.5 eq.) were suspended in DMSO (10 mL). It was heated to 70 °C for 15 h. The mixture was cooled to 20-25°C. A 40% aq. solution of citric acid was added dropwise (20 mL), followed by DCM (20 mL). The layers were separated and the org. phase was washed with brine (20 mL) and water (10 mL). The combined org. layers were concentrated under reduced pressure to a residual volume of approx. 20 mL. It was cooled to 0-5°C, washed with cold DCM (5 mL), filtered and dried under reduced pressure (40°C, 10 mbar) to afford the title compound as a white solid (1.51 g, 65% yield).
  • Example 1 The compound of Example 1 (10 g; 20.6 mmol), propylsulfamide (3.1 g; 22.6 mmol; 1.1 eq.; prepared as described in Bolli et al., J. Med. Chem. (2012), 55, 7849-7861 ), TBAF.3H 2 O (19.5 g; 61.7 mmol; 3 eq.) and potassium carbonate (8.5 g; 61.7 mmol; 3 eq.) were suspended in DMSO (100 mL). The mixture was heated to 100°C for 1 h and then cooled to 20-25°C. Water (100 mL) and DCM (100 mL) were added. The org.
  • Example 2 The compound of Example 2 (14 g; 28.7 mmol), benzylsulfamide potassium salt (7.09 g; 31.6 mmol; 1.1 eq.; prepared as described in Bolli et al., J. Med. Chem. (2012), 55, 7849-7861 ), TBAF.3H 2 O (27.2 g; 86.2 mmol; 3 eq.) and potassium carbonate (15.9 g; 115 mmol; 4 eq.) were suspended in DMSO (140 mL) at 20-25°C. The mixture was heated to 100-105°C for 1 h. At this point, LC-MS (method 1) indicated complete conversion. The reaction mixture was cooled to 10-15°C. Water (140 mL) and DCM (140 mL) were added.

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Claims (10)

  1. Procédé de fabrication du composé de formule I
    Figure imgb0032
     où R représente un H, ou un sel de celui-ci, ledit procédé comprenant la réaction du composé de formule I-1
    Figure imgb0033
     où X représente un brome, un chlore ou un fluor, avec le composé de formule I-2
    Figure imgb0034
     où R représente un H, ou un sel dudit composé de formule I-2, ladite réaction étant effectuée en la présence d'une base dans un solvant organique aprotique polaire ou un mélange polaire de solvants organiques aprotiques et, quand X représente un brome ou un chlore, en la présence d'hydrate de fluorure de tétra-n-butylammonium ou de fluorure de césium.
  2. Procédé de la revendication 1, où la base est sélectionnée dans le groupe consistant en les suivantes : NaOH, KOH, 1,8-diazabicyclo[5.4.0]undéc-7-ène, triéthylamine, tert-butylate de potassium, Na2CO3, K2CO3 et Cs2CO3.
  3. Procédé de la revendication 2, où la base est K2CO3.
  4. Procédé de l'une des revendications 1 à 3, où le solvant organique aprotique polaire ou le mélange polaire de solvants organiques aprotiques comprend le diméthylsulfoxyde.
  5. Procédé de la revendication 4, qui est effectué en utilisant le diméthylsulfoxyde comme solvant.
  6. Procédé de l'une des revendications 1 à 5, où X représente un chlore et où la réaction du composé de formule I-1 avec le composé de formule I-2 est effectuée en la présence d'hydrate de fluorure de tétra-n-butylammonium et en utilisant le diméthylsulfoxyde comme solvant.
  7. Composé de formule I-1
    Figure imgb0035
     où X représente un fluor ;
    ou sel dudit composé.
  8. Utilisation d'un composé de formule I-1 selon la revendication 7 ou d'un sel de celui-ci dans un procédé de fabrication du composé de formule I tel que défini à la revendication 1 ou d'un sel de celui-ci.
  9. Procédé de fabrication du composé de formule I
    Figure imgb0036
     où R représente un H, ou de fabrication d'un sel de celui-ci, ledit procédé comprenant les étapes suivantes :
    a) la réaction du composé de formule I-lci
    Figure imgb0037
     ou d'un sel de celui-ci, avec l'hydrate de fluorure de tétra n-butylammonium ou le fluorure de césium en la présence d'une base dans un solvant organique aprotique polaire ou un mélange polaire de solvants organiques aprotiques pour obtenir le composé de formule I-1F
    Figure imgb0038
     et
    b) la réaction du composé de formule I-1F obtenu à l'étape a) avec un composé de formule I-2
    Figure imgb0039
     où R représente un H, ou un sel de celui-ci, en la présence d'une base dans un solvant organique aprotique polaire ou un mélange polaire de solvants organiques aprotiques pour obtenir ledit composé de formule I ou sel de celui-ci.
  10. Procédé de la revendication 9, où l'étape a) est effectuée par réaction du composé de formule I-1C1 avec le fluorure de césium.
EP15706185.4A 2014-02-14 2015-02-13 Procédé de fabrication de dérivés de pyrimidine sulfonamide Active EP3105220B1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP17159638.0A EP3214082B1 (fr) 2014-02-14 2015-02-13 Procédé de fabrication de dérivés de sulfamide de pyrimidine
SI201531349T SI3105220T1 (sl) 2014-02-14 2015-02-13 Postopek za proizvodnjo pirimidin sulfamidnih derivatov
PL15706185T PL3105220T3 (pl) 2014-02-14 2015-02-13 Sposób wytwarzania pochodnych pirymidynosulfonoamidowych
HRP20201450TT HRP20201450T1 (hr) 2014-02-14 2020-09-10 Postupak za proizvodnju derivata pirimidin-sulfamida

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP14155137.4A EP2907811A1 (fr) 2014-02-14 2014-02-14 Procédé de fabrication de dérivés de sulfamide de pyrimidine
PCT/EP2015/053047 WO2015121397A1 (fr) 2014-02-14 2015-02-13 Procédé de fabrication de dérivés de pyrimidine sulfonamide

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EP17159638.0A Division-Into EP3214082B1 (fr) 2014-02-14 2015-02-13 Procédé de fabrication de dérivés de sulfamide de pyrimidine

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EP3105220A1 EP3105220A1 (fr) 2016-12-21
EP3105220B1 true EP3105220B1 (fr) 2020-07-01

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EP15706185.4A Active EP3105220B1 (fr) 2014-02-14 2015-02-13 Procédé de fabrication de dérivés de pyrimidine sulfonamide
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US (1) US9938244B2 (fr)
EP (3) EP2907811A1 (fr)
JP (2) JP6431922B2 (fr)
KR (2) KR102261695B1 (fr)
CN (2) CN105992762B (fr)
AR (2) AR099434A1 (fr)
AU (2) AU2015217000B2 (fr)
BR (2) BR122017005939B1 (fr)
CA (1) CA2937277C (fr)
CL (2) CL2016002008A1 (fr)
CY (1) CY1123319T1 (fr)
DK (1) DK3105220T3 (fr)
EA (2) EA032460B1 (fr)
ES (2) ES2906458T3 (fr)
HK (1) HK1243405A1 (fr)
HR (1) HRP20201450T1 (fr)
HU (1) HUE050974T2 (fr)
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LT (1) LT3105220T (fr)
MX (1) MX368014B (fr)
NZ (1) NZ724273A (fr)
PL (1) PL3105220T3 (fr)
PT (1) PT3105220T (fr)
SA (1) SA516371640B1 (fr)
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SI (1) SI3105220T1 (fr)
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AR095727A1 (es) 2013-03-27 2015-11-04 Actelion Pharmaceuticals Ltd Preparación de intermediarios de pirimidina
EP2907811A1 (fr) * 2014-02-14 2015-08-19 Actelion Pharmaceuticals Ltd. Procédé de fabrication de dérivés de sulfamide de pyrimidine
CN105461638A (zh) * 2015-12-10 2016-04-06 合肥久诺医药科技有限公司 一种马西替坦晶型及其制备方法
CN105461639B (zh) * 2015-12-10 2018-03-09 合肥久诺医药科技有限公司 一种高纯度马西替坦的精制方法
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CL2017000505A1 (es) 2017-11-24
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